Interferon-a (IFN) is the only approved medication for hepatitis C viral (HCV) infection. However, side effects associated with IFN therapy represent a major obstacle to adequate treatment for patients with HCV, often resulting in the discontinuation IFN therapy. It is hypothesized that common mechanisms contribute to IFN-induced depression and antiviral effects. Two of IFN's antiviral mechanisms, 1) activation of inducible nitric oxide synthase (iNOS) and 2) induction of indoleamine 2,3-dioxygenase, which depletes tryptophan, involve mechanisms also hypothesized to cause depression. To accomplish the objectives of this grant, three specific aims will be pursued: 1) determine how plasma nitrite, tryptophan, and serotonin levels relate to IFN therapeutic response and depressive symptoms; 2) identify the effects of iNOS inhibition and serotonergic antidepressants on the proliferative response of T cells to HCV-derived antigens; and 3) evaluate antidepressant treatment on IFN-induced biochemical and therapeutic effects. Results will contribute to knowledge of IFN mechanisms that are important in HCV and in understanding depressive symptoms accompanying medical conditions where cytokines are elevated.